Infections with oncogenic types of HPV cause virtually all cases of cervical cancer worldwide and subsets of various other anogenital and head and neck cancers. Prophylactic vaccination against HPV-16 and HPV-18, two of the most important HPV types, could protect against a large majority of the cases of cervical cancer globally and a considerable proportion of other HPV-associated cancers. Vaccines based on the L1 structural protein of HPV that self-assemble into conformationally-correct VLPs have been shown to be generally safe, immunogenic and effective at preventing precancerous lesions of the cervix associated with HPV-16/18. A community-based phase 3 randomized controlled trial of an HPV16/18 VLP vaccine was conducted in Costa Rica. Costa Rica was chosen for the trial because of our extensive successful scientific collaborations there, the high risk of cervical cancer, the universal medical system providing national linkage, and the likelihood of very high participation over the many needed years of close clinical follow-up. Randomization and 3-dose vaccination of 7,466 women enrolled into the HPV-16/18 Vaccine Trial in Costa Rica has been successfully completed. Women have been followed actively on an annual or semi-annual basis in the first four years of follow-up and every two years thereafter. Women have completed their first four years of follow-up in the blinded phase of the trial and have been enrolled in the extended (up to 10 years) follow-up phase of the study. Cross-over vaccination was offered to trial participants at the end of the four-year blinded phase of the trial. Results from this study have shown that 1) the vaccine is highly effective at preventing new infections with HPV types 16 or 18, 2) the vaccine confers partial protection against HPV types phylogenetically related to HPV 16 or 18, 3) the vaccine does not help treat existing infections, 4) fewer than 3 doses of the vaccine protects as well as the full 3-dose series for at least 4 years, 5) the vaccine protects against HPV infection at the anus, 6) Vaccine impact declines with increasing age at vaccination, 7) vaccination induces cross-neutralizing potential in sera of vaccinated individuals, 8) modest levels of antibodies generated by natural HPV infection provide partial protection against re-infection, and 9) antibody levels generated in vaccines from regions with high HIV infection rates are comparable to those observed among participants in our trial in Costa Rica. In support of the vaccine trials, a variety of methodologic and ancillary projects are underway or planned, that will maximize the yield of the main effort. This includes evaluation of immunological correlates of protection, including viral neutralization, total type-specific antibodies, and measures of antibody avidity. Immunological correlates of protection among naturally infected women are being examined and studies are underway to better understand why vaccinated women might be protected against HPV types not included in the vaccine formulation and why a single vaccine dose (prime-only) appears to protect for several years. Several analyses are underway or planned to evaluate the natural history of HPV infection at cervical and other sites and of cervical neoplasia in vaccinated and unvaccinated women. This effort is sponsored by Intramural NCI funds and by the NIH Office of Research on Women's Health (ORWH). It was formerly associated with Project Z01 CP010177.